Gastroenterology

Gastroenterology

Volume 160, Issue 1, January 2021, Pages 317-330.e11
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Elucidation of Proteus mirabilis as a Key Bacterium in Crohn’s Disease Inflammation

https://doi.org/10.1053/j.gastro.2020.09.036Get rights and content
Under a Creative Commons license
open access

Background & Aims

Proteus spp, Gram-negative facultative anaerobic bacilli, have recently been associated with Crohn’s disease (CD) recurrence after intestinal resection. We investigated the genomic and functional role of Proteus as a gut pathogen in CD.

Methods

Proteus spp abundance was assessed by ure gene–specific polymerase chain in 54 pairs of fecal samples and 101 intestinal biopsies from patients with CD and healthy controls. The adherence, invasion, and intracellular presence of 2 distinct isolates of Proteus mirabilis in epithelial cells were evaluated using immunofluorescence and electron microscopy. Intracellular gene expression profiles and regulated pathways were analyzed by RNA sequencing and KEGG pathway analysis. Biologic functions of 2 isolates of P mirabilis were determined by in vitro cell culture, and in vivo using conventional mice and germ-free mice.

Results

Proteus spp were significantly more prevalent and abundant in fecal samples and colonic tissue of patients with CD than controls. A greater abundance of the genus Fusobacterium and a lesser abundance of the genus Faecalibacterium were seen in patients with CD with a high Proteus spp abundance. All 24 Proteus monoclones isolated from patients with CD belonged to members of P mirabilis lineages and 2 isolates, recovered from stool or mucosa, were used in further studies. Mice gavaged with either P mirabilis strain had more severe colonic inflammation. Co-culture of the isolates with epithelial cell lines showed bacterial adherence, invasion, increased production of pro-inflammatory cytokines IL-18 and IL-1α, and cell necrosis. Both isolates induced key pro-inflammatory pathways, including NOD-like receptor signaling, Jak-STAT signaling, and MAPK signaling, and induced pro-inflammatory genes and activated inflammation-related pathways in gnotobiotic mice.

Conclusions

P mirabilis in the gut is associated with CD and can induce inflammation in cells and animal models of colitis. P mirabilis can act as a pathobiont and play a crucial role in the pathogenesis of CD.

Keywords

P mirabilis
Crohn’s Disease
Inflammation
Pathogen

Abbreviations used in this paper

CD
Crohn’s disease
cfu
colony-forming units
DSS
dextran sulfate sodium
qPCR
quantitative polymerase chain reaction

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Conflicts of interest The authors disclose no conflicts.

Funding Supported by The Leona M. and Harry B. Helmsley Charitable Trust and Croucher Senior Medical Research Fellowship. The Translational Research Institute is funded by a grant from the Australian Federal Government.

Author names in bold designate shared co-first authorship.